Scientists have deciphered a key component of the language used by cells to orchestrate responses to their external environment. Mathematical and experimental analyses have discovered patterns in the changes of calcium ion concentrations within cells that allow reliable signalling to a diverse range of cellular activities.
One of the most common ways that cells respond to their external environment is through changes in the concentration of a tiny charged particle, the calcium ion (Ca2+). Cells work hard to exclude calcium ions, so that concentrations inside the cell are low. However, stimuli in the external environment, such as hormones, allow calcium to flow briefly back into the cell through tiny pores, each with its own regulated gate. By transforming signals outside of the cell into calcium changes within the cell, cells can respond to their environment.
Repetitive calcium spikes occur in many cells in response to extracellular stimuli. These 'spikes' of calcium ions within individual cells last no more than a few seconds before the calcium concentration recovers to its resting level. The frequency of these calcium spikes often increases with stimulus intensity, sustaining a belief that the cell reads these spikes as a digital code. So, just as it is easier for us to distinguish black spots on a white background, rather than between shades of grey, cells may respond to the number of calcium spikes, rather than to graded changes in the concentration of calcium.
But, as Thurley et al now report in Science Signaling¸ different cells exposed to identical stimuli respond with very different frequencies of calcium spikes, and there is random variation in the intervals between calcium spikes in each cell.
With such inherent variability, the researchers questioned how cells might respond reliably to changes in extracellular stimulus intensity.
The new work, which combines experimental and mathematical analyses, found that two conserved mechanisms allow cells to transmit information via calcium spikes with considerable reliability.
Professor Taylor, University of Cambridge, who contributed to the study said: "It's like deciphering a coded message. We knew that the concentration of calcium ions was transmitting a message, but we didn't know how. A problem is that very small numbers of molecules initiate the calcium spikes, causing them to be random and variable. How then might calcium spikes usefully transmit information? Mathematical modelling prompted experiments that lead us towards an answer."
The average interval between Ca2+ spikes (interspike interval) differs considerably between cells trated with the same stimulus, but there is a consistent relationship when the response to changes in stimulus intensity are examined. The percentage change in the interval between calcium spikes responding to steps in stimulus intensity is consistent for all cells. The 'fold change' in the random component of the interval between calcium spikes is the same for all cells, and it encodes the change in stimulus intensity.
This suggests that cells might more reliably detect changes in extracellular stimulus intensity if they ignore absolute spike frequencies, and instead read conserved fold-changes in the random component of the interval between spikes.
Professor Taylor explains: "There is an appealing musical analogy. We recognise a melody whether it is played by a cellist or violinist, even though the pitch is different. So too with cells responding to extracellular stimuli: the melody (the fold change in the random component of the gap between Ca2+ spikes) conveys the message, not the pitch (the frequency of the calcium spikes).
Notes to editors
The paper by K. Thurley, S.C. Tovey, G. Moenke, V. L. Prince, A. Meena, A. P. Thomas, A. Skupin, C. W. Taylor, M. entitled Falcke, Reliable encoding of stimulus intensities within random sequences of intracellular Ca2+ spikes is published in Science Signaling (2014)